{
  "abstract": "Background Leptomeningeal disease (LMD) is a devastating complication of breast cancer (BC) and occurs in ˜5% of patients and has a poor prognosis. The CSF of patients with LMD have an innate, but not adaptive, immuno cellular profile. We found in murine LMD models IT cDC1s were safe, induced a Th1 response, cured most HER2+ LMD, and prevented LMD recurrence. This provoked a Th1 response, was CD4+ > CD8+ T cell and B cell dependent. We hypothesized in BC LMD patients that a RP2D would be identified, and the CSF would be remodeled to have a Th1 adaptive immunological profile identified by transcriptomic analysis.Methods This is a phase I dose escalation study ( NCT05809752) that establishes 1) safety and 2) associations between clinical outcomes & translational CSF studies. Eligibility includes TNBC or HER+ LMD pts, prior pCSpRT/WBRT, ECOG PS ≤2, normal marrow and organ function and ommaya reservoir. IT cDC1 IT were administered weekly x 12 (1 x 106 – 5 x 107) until PD, DLT or withdrawal. Endpoints were 1) the safety/MTD, and 2) association between clinical and immune profiles in the CSF. DLTs were defined as ≥ gr. 3 not due to LMD. Final pre & post cDC1 treatment cyto-, chemokine profiles and cellular/tumor profiles (scRNA-seq) were determined.Results As of 6/24/25, the first 6 patients in whom transcriptomics was possible, received 1 x 10 6 – 2 x 107 DCs weekly without DLTs. Headaches were common and grade 3 in two (33%) patients. Performance status remained stable or improved in five (83%) patients. Two (33%) had PD of LMD. At follow-up, one patient died from RT leukoencephalopathy. The median OS was 15 mos and five (83%) are alive. A focused clinical cytokine panel showed marked elevation of CSF Th1 cytokines: IFN-g (2. 5 - 5.2 x ULN), IL-6 (16.9 - 220 x ULN), IL-12 (3 -9.7 X ULN), TNF-a (14 - 34 X ULN); the Th2-related IL-4 was not elevated. Transcriptomic analyses of CSF showed a remodeled environment with marked increase in CD4+ T, CD8+ T and B cells with a reduction of tumor cells. Antibodies to HER2 or HER3 developed in four of five (80%) patients.Conclusions Our results suggest that this activates a CD4+ Th1 adaptive immune responses that drives adaptive antitumor activity which is otherwise lacking in LMD ( NCT05809752). Mechanistic studies are in progress.",
  "authors": [
    {
      "affiliations": [
        "H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA"
      ],
      "name": "Peter Forsyth"
    },
    {
      "affiliations": [
        "H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA"
      ],
      "name": "Vincent Law"
    },
    {
      "affiliations": [
        "H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA"
      ],
      "name": "Kamran Ahmed"
    },
    {
      "affiliations": [
        "H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA"
      ],
      "name": "Piteo Cecily"
    },
    {
      "affiliations": [
        "H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA"
      ],
      "name": "Brittany Evernden"
    },
    {
      "affiliations": [
        "H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA"
      ],
      "name": "Yolanda Pina"
    },
    {
      "affiliations": [
        "H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA"
      ],
      "name": "Inna Smalley"
    },
    {
      "affiliations": [
        "H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA"
      ],
      "name": "Nam Tran"
    },
    {
      "affiliations": [
        "H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA"
      ],
      "name": "Brian Czerniecki"
    },
    {
      "affiliations": [
        "University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"
      ],
      "name": "Pawel Kalinski"
    }
  ],
  "title": "349 A transcriptomic analysis of a first in human phase I trial of intrathecal dendritic cells in patients with leptomeningeal disease show development of adaptive immune responses",
  "uid": "f1a76c3a-2940-57cd-b151-d1b35b821b27"
}